Cited by 9Hematopoietic Stem Cell TransplantationGenomics and Chromatin DynamicsGene Regulatory Network Analysis

Blood stem cell PU.1 upregulation is a consequence of differentiation without fast autoregulation

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Ahmed, Nouraiz, Etzrodt, Martin, Dettinger, Philip, Kull, Tobias, Loeffler, Dirk, Hoppe, Philipp S., Chavez, James S., Zhang, Yang +5 more·2022·Journal of Experimental Medicine

Abstract

Transcription factors (TFs) regulate cell fates, and their expression must be tightly regulated. Autoregulation is assumed to regulate many TFs' own expression to control cell fates. Here, we manipulate and quantify the (auto)regulation of PU.1, a TF controlling hematopoietic stem and progenitor cells (HSPCs), and correlate it to their future fates. We generate transgenic mice allowing both inducible activation of PU.1 and noninvasive quantification of endogenous PU.1 protein expression. The quantified HSPC PU.1 dynamics show that PU.1 up-regulation occurs as a consequence of hematopoietic differentiation independently of direct fast autoregulation. In contrast, inflammatory signaling induces fast PU.1 up-regulation, which does not require PU.1 expression or its binding to its own autoregulatory enhancer. However, the increased PU.1 levels induced by inflammatory signaling cannot be sustained via autoregulation after removal of the signaling stimulus. We conclude that PU.1 overexpression induces HSC differentiation before PU.1 up-regulation, only later generating cell types with intrinsically higher PU.1.

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Crossref · 10.1084/jem.20202490

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  • Increased PU.1 expression triggers enhanced activation of myeloid differentiation pathways in HSPC, leading to increased myeloid cell output, sometimes referred to as myeloid-biased hematopoiesis.

    “Increased PU.1 expression in turn triggers enhanced activation of myeloid differentiation pathways in HSPC, leading to increased myeloid cell output, sometimes referred to as “myeloid-biased” hematopoiesis (Pietras et al., 2016; Rabe et al., 2020; Ahmed et al., 2022; Chavez et al., 2022).”

    From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Ahmed et al., 2022

    The Results and discussion section reports that PU.1 overexpression induced myeloid differentiation in HSCs and that PU.1 activation redirected megakaryocyte-erythrocyte progenitors toward the granulocyte-monocyte lineage. It does not establish the claimed increase in myeloid cell output or measure enhanced activation of myeloid differentiation pathways; it also concludes that PU.1 upregulation during HSPC differentiation is a consequence of differentiation rather than its initiating mechanism. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • Inflammation-induced signals can trigger PU.1 expression independently of the −14 kb URE PU.1 autoregulatory binding site.

    “likely reflecting the capacity of inflammation-induced signals to trigger PU.1 expression independently of the −14 kb URE PU.1 autoregulatory binding site (Ahmed et al., 2022).”

    From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Ahmed et al., 2022

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Authors
Ahmed, N., Etzrodt, M., Dettinger, P., Kull, T., Loeffler, D., Hoppe, P. S., Chavez, J. S., Zhang, Y., Camargo Ortega, G., Hilsenbeck, O., Nakajima, H., Pietras, E. M., & Schroeder, T.
Affiliations
  • ETH Zurich (CH)
  • Department of Biosystems Science & Engineering, Eidgenössische Technische Hochschule Zürich, Basel, Switzerland 1
  • University of Colorado Anschutz (US)
  • Yokohama City University (JP)
Corresponding author
Schroeder, Timm
Venue
Journal of Experimental Medicine
Published
2021-11-24
Volume
219
Issue
1
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W3215312371
Cited by
9
References
61
Citations by year
2025: 1 · 2024: 1 · 2023: 2 · 2022: 5
FWCI
1.31
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-sa)
  • ETH Zürich Research Collection
Funders
  • Swiss National Science Foundation (179490)
  • European Molecular Biology Organization
  • Eidgenössische Technische Hochschule Zürich (R01 DK119394)
  • SystemsX.ch
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
PU.1, hematopoietic stem and progenitor cells, autoregulation, transcription factor regulation, hematopoietic differentiation, inflammatory signaling, transgenic mice, cell fate determination, enhancers
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Cells, Cultured, Hematopoietic Stem Cells, Homeostasis, Male, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Proto-Oncogene Proteins, Signal Transduction, Trans-Activators, Up-Regulation, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, Mice, Time-Lapse Imaging

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